Endocrine Abstracts

GH receptor stimulation changes intracellular protein phosphorylation and activates the JAK-STAT signalling pathway. The JAK2 - STAT5 components of this pathway seem critical for growth. Factors of essence for cellular effects of GH include the duration of GH receptor stimulation and in different species there are sex differences in GH secretion where males have an episodic and females have a more continuous mode of GH secretion. At the cellular level, these two types of GH secretion cause different gene expression patterns to emerge and this is in particular the case for GH effects on the liver. GH controls important aspects of liver metabolism and it is interesting to note that some of these seem to depend on the secretory GH pattern. Another aspect of GH signaling is that the duration of GH receptor signals is related to changes in SOCS (suppression of cytokine signaling) expression. The SOCS proteins seem to be part of an intracellular feed back loop that silence GH signals. In our studies, SOCS2 appears to be a key intracellular regulator of GH sensitivity since elimination of SOCS2 creates a situation of increased GH sensitivity. Our working hypothesis is that SOCS2 ubiqitinates the GH receptor and thereby causes its proteasomal degradation. The concept that SOCS2 is a part of an ubiquitin ligase complex is substantiated by structural and biochemical findings. Furthermore, the gene targets for GH induced signals include the SOCS2 gene. In this gene we have characterized STAT 5 DNA binding elements in proximity to another transcription factor binding site that is unique for SOCS2 the SOCS protein family. In summary our data suggest that the liver is an important tissue for GH to exert metabolic regulation and that SOCS2 is a component that determines GH sensitivity.